Early exercise protects the blood-brain barrier from ischemic brain injury via the regulation of MMP-9 and occludin in rats.

Abstract

Early exercise within 24 h after stroke can reduce neurological deficits after ischemic brain injury. However, the mechanisms underlying this neuroprotection remain poorly understood. Ischemic brain injury disrupts the blood-brain barrier (BBB) and then triggers a cascade of events, leading to secondary brain injury and poor long-term outcomes. This study verified the hypothesis that early exercise protected the BBB after ischemia. Adult rats were randomly assigned to sham, early exercise (EE) or non-exercise (NE) groups. The EE and NE groups were subjected to ischemia induced by middle cerebral artery occlusion (MCAO). The EE group ran on a treadmill beginning 24 h after ischemia, 30 min per day for three days. After three-days' exercise, EB extravasation and electron microscopy were used to evaluate the integrity of the BBB. Neurological deficits, cerebral infarct volume and the expression of MMP-9, the tissue inhibitors of metalloproteinase-1 (TIMP-1), and occludin were determined. The data indicated that early exercise significantly inhibited the ischemia-induced reduction of occludin, and an increase in MMP-9 promoted TIMP-1 expression (p < 0.01), attenuated the BBB disruption (p < 0.05) and neurological deficits (p < 0.01) and diminished the infarct volume (p < 0.01). Our results suggest that the neuroprotection conferred by early exercise was likely achieved by improving the function of the BBB via the regulation of MMP-9 and occludin.

Effect of early exercise on the expression of TIMP-1 protein following focal cerebral ischemia. (A) Representative bands of TIMP-1 expression in ischemic brains following MCAO detected by Western blotting; (B) Quantification of the optical density of the TIMP-1 bands, normalized to GAPDH. The low TIMP-1 levels induced by MCAO were increased by early exercise. **p < 0.01, compared with the NE group; # p < 0.05 and ## p < 0.01, compared with the sham group. n = 6.

Effect of early exercise on the expression of occludin protein following focal cerebral ischemia. (A) Representative bands of occludin expression in ischemic brains following MCAO detected by Western blotting; (B) Quantification of the optical density of the occludin bands, normalized to beta-actin. There was a significant upregulation of occludin expression in the EE group. *p < 0.05 and **p < 0.01, compared with the NE group; # p < 0.05 and ## p < 0.01, compared with the sham group. n = 6.